6u9b: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6u9b is ~~ON HOLD~~ ~~until Paper~~ Publication

==Hsp90a NTD covalently bound to sulfonyl fluoride 5 at K58==

== Structural highlights ==

<table><tr><td colspan='2'>[[6u9b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U9B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U9B FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q2A:3-{[(3S)-3-({6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}methyl)piperidin-1-yl]methyl}benzene-1-sulfonyl+fluoride'>Q2A</scene></td></tr>

<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6u99|6u99]], [[6u98|6u98]], [[6u9a|6u9a]]</td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6u9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u9b OCA], [http://pdbe.org/6u9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u9b RCSB], [http://www.ebi.ac.uk/pdbsum/6u9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u9b ProSAT]</span></td></tr>

</table>

== Function ==

[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>

== Publication Abstract from PubMed ==

Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.

~~Authors~~:

Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.,Cuesta A, Wan X, Burlingame AL, Taunton J J Am Chem Soc. 2020 Feb 3. doi: 10.1021/jacs.9b09684. PMID:32009391<ref>PMID:32009391</ref>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Cuesta, A]]

[[Category: Taunton, J]]

[[Category: Wan, X]]

[[Category: Chaperone]]

[[Category: Chaperone-inhibitor complex]]

[[Category: Inhibitor]]

[[Category: Lysine-targeted inhibitor]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6u9b is ON HOLD  until Paper Publication
+==Hsp90a NTD covalently bound to sulfonyl fluoride 5 at K58==
+<StructureSection load='6u9b' size='340' side='right'caption='[[6u9b]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6u9b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U9B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U9B FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=Q2A:3-{[(3S)-3-({6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}methyl)piperidin-1-yl]methyl}benzene-1-sulfonyl+fluoride'>Q2A</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6u99|6u99]], [[6u98|6u98]], [[6u9a|6u9a]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6u9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u9b OCA], [http://pdbe.org/6u9b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u9b RCSB], [http://www.ebi.ac.uk/pdbsum/6u9b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u9b ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.
-Authors:
+Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90.,Cuesta A, Wan X, Burlingame AL, Taunton J J Am Chem Soc. 2020 Feb 3. doi: 10.1021/jacs.9b09684. PMID:32009391<ref>PMID:32009391</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6u9b" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Cuesta, A]]
+[[Category: Taunton, J]]
+[[Category: Wan, X]]
+[[Category: Chaperone]]
+[[Category: Chaperone-inhibitor complex]]
+[[Category: Inhibitor]]
+[[Category: Lysine-targeted inhibitor]]